Recently, with the rapid increase of aged population, Alzheimer's disease has become an important social issue. Alzheimer's disease is a serious social and economical concern which devastates the patient's life and ruins those of his/her families. According to the Alzheimer's Association, 10.3% of the people aged 65 years or above are suffering from dementia, and 95 billion dollars are expended every year in treating dementia. And, according to a report by the Korea Health Industry Development Institute, the prevalence of the illness is about 8.3% of the people aged 65 years or above, with more than 340,000, in Korea, as of 2000 (reported on May 10, 2005 in Seoul Shinmun).
Dementia is defined as the decline in memory and cognitive function thereby causing troubles in daily activities. It may be largely classified into vascular dementia and senile dementia. Vascular dementia is associated with cerebral hemorrhage, stroke, etc. mainly caused thrombosis. It is known that memory loss or other symptoms occur as the brain cells around the hemorrhage site are damaged. Senile dementia, a.k.a. Alzheimer's disease, prevails over vascular dementia in frequency, and is known to be caused by the accumulation of β-amyloid in the brain and the continued damage of nerve cells resulting from its toxicity [Gandy et al., J. Clin. Invest., 2005]. It is reported that oxygen radicals play an important function in the process [Zhu et al., Brain Research, 2004]. It is also reported that inflammatory response is related with the onset of Alzheimer's disease, which is evidenced by the fact that the occurrence of Alzheimer's disease decreases when non-steroidal anti-inflammatory drugs are administered [Gasparini et al., Brain Research Reviews, 2005].
Down's syndrome is a genetic disorder caused by the presence of an extra 21st chromosome. As it is reported that a larger amount of amyloid protein is accumulated in the brains of Down's syndrome patients than normal people, amyloid is known to be related with Down's syndrome [Crystal et al., Neurobiology of Aging, 1997, Yasuhiro et al., Brain & Development, 1997].
Defective memory, which is one of the symptoms of Alzheimer's disease, is reported to be closely related with the cholinergic nervous system. Exposure to organophosphorus compounds at low concentration induces abnormal activation of acetylcholinesterase, leading to decreased acetylcholine and inefficient transmission thereof. It is also reported that accumulation of β-amyloid causes toxicity in the brain cells and lower memory function [Small et al., Curr. Alzheimer Res., 2004].
Mild cognitive impairment is a term coined by neuroscientists to refer to the individuals who have cognitive impairments beyond that expected for their age and education, but that do not interfere significantly with their daily activities. It is considered to be the boundary or transitional stage between normal aging and dementia. Scientists have classified the patients who show poor memory for their age but do not show the symptoms of Alzheimer's disease, and diagnosed them as mild cognitive impairment. Those who are diagnosed with mild cognitive impairment need to get help from experts for more accurate diagnosis and treatment, because these individuals tend to progress to Alzheimer's disease. Recently, a research is under way to see if vitamin E and acetylcholinesterase inhibitor are effective for the patients with mild cognitive impairment. This research monitors if the administration of vitamin E or acetylcholinesterase inhibitor can reduce the percentage of the patients with mild cognitive impairment to progress to Alzheimer's disease.
Amyloidosis is also called amyloid degeneration. The name amyloid comes from the early mistaken identification of the substance as starch (ainylum in Latin). Amyloid is a semitransparent wax. When stained with a purple pigment, it exhibits a red color. The substance is frequently found in blood vessel walls or nearby fibers, between spleen or liver cells, or between interstitial tissues of heart muscles or glossal muscles. When the amyloid proteins are in small quantity, it is called amyloid degeneration. But, when they are abnormally deposited in organs and/or tissues, it is called amyloidosis.
At present, cholinesterase inhibitors, e.g., Tacrine, Aricept and Exelon, which reduce the breakdown of choline at synapses and thereby increase the quantity of choline in the brain, are used to treat or ameliorate Alzheimer's disease. However, the effect is only slight and temporary, and many side effects including liver toxicity are involved [Forchetti et al., Prim. Care Companion J. Clin. Psychiatry, 2005].
A large number of research institutes worldwide have tried to find a cure for Alzheimer's disease and other amyloid-related diseases. There have been efforts to find substances that inhibit the generation of β-amyloid or those that inhibit the apoptosis of nerve cells.
4-O-methylhonokiol was first isolated in 1978 [El-Feraly, F. S. et al., Lloydia, 41, p. 493, 1978]. Like magnolol, 4-O-methylhonokiol is known to antibacterial effect and insecticidal effect against mosquito larva and brine shrimp [Nitao J. K. et al., Phytochemistry, 30, p. 2193, 1991]. But, there is no research on the treatment or prevention of Alzheimer's disease or other amyloid-related diseases with 4-O-methylhonokiol.
The inventors of the present disclosure have found out for the first time that 4-O-methylhonokiol inhibits the production of β-amyloid. It has been confirmed to be useful in treating or preventing amyloid-related diseases. Through animal tests including water maze test and passive avoidance test on mice, 4-O-methylhonokiol has been confirmed to be effective for amyloid-related diseases such as Alzheimer's disease, defective memory, cognitive disorder, and the like. It was further confirmed through acetylcholinesterase activity inhibition test using mouse brain cortex and hippocampus tissue that they are particularly effective in treating or preventing Alzheimer's disease among the amyloid-related diseases.